Background: Everolimus (EVE) plus exemestane (EXE) doubled PFS while maintaining quality of life versus EXE alone in postmenopausal hormone receptor-positive (HR⁺), HER2-negative metastatic breast cancer (MBC) (BOLERO-2 phase 3; NCT00863655). Here we investigated several serum biomarkers of inflammation: ferritin, interleukin-8 (IL-8), and tumor necrosis factor receptor 1 (TNFR1). Both higher IL-8 (ASCO 2018, #3025) and TNF (Nature 569:428-32, 2019) have been reported to be associated with worsened outcome to immune checkpoint inhibitors (ICI), and IL-8- and TNF-targeted therapies combined with ICIs are in phase I trials. We evaluated the prognostic/predictive ability of serum ferritin, IL-8, and TNFR1 to everolimus in BOLERO-2. Methods: Serum biomarkers were determined on pretreatment serum samples using the ELLA immunoassay platform (ProteinSimple, San Jose, CA). Cox-proportional hazards model was used to assess the efficacy of EVE, and the prognostic and predictive effect on PFS and OS. Results: Pretreatment serum biomarker levels were determined in 510 patients (70 %) of 725 BOLERO-2 patients randomized 2:1 to EVE+EXE or EXE). Serum levels (25%, 50%, 75%) were: ferritin (68.9, 125.5, 253.1 ng/ml); IL-8 (14.5, 19.4, 27.7 pg/ml); and TNFR1 (1205, 1470, 1868 pg/ml). Ferritin correlated significantly with TNFR1 (r=0.45, p<0.0001), while IL-8 correlated weakly with TNFR1 (r=0.10, p=0.023). Higher levels of all 3 biomarkers were prognostic for significantly shorter PFS and OS (table). But no biomarkers were predictive: everolimus was efficacious regardless of the 3 biomarker levels (p>0.05). Conclusions: High levels of serum ferritin, IL-8, and TNFR1 were significantly associated with shorter PFS and OS in HR+/HER2- MBC patients. Everolimus had superior outcomes compared to placebo, regardless of serum biomarker level. These 3 significant prognostic biomarkers are all associated with increased inflammatory processes through different pathways. Anti-inflammatory therapy targeted against these biomarkers should be evaluated based on serum level as potential combination therapy with everolimus or CDK 4/6 inhibitors in HR+ MBC.